Biocompatibility: Meeting a Key Functional Requirement of Next-Generation Medical Devices

Abstract

The array of polymeric, biologic, metallic, and ceramic biomaterials will be reviewed with respect to their biocompatibility, which has traditionally been viewed as a requirement to develop a safe medical device. With the emergence of combination products, a paradigm shift is occurring that now requires biocompatibility to be designed into the device. In fact, next-generation medical devices will require enhanced biocompatibility by using, for example, pharmacological agents, bioactive coatings, nanotextures, or hybrid systems containing cells that control biologic interactions to have desirable biologic outcomes. The concept of biocompatibility is moving from a “do no harm” mission (i.e., nontoxic, nonantigenic, nonmutagenic, etc.) to one of doing “good,” that is, encouraging positive healing responses. These new devices will promote the formation of normal healthy tissue as well as the integration of the device into adjacent tissue. In some contexts, biocompatibility can become a disruptive technology that can change therapeutic paradigms (e.g., drug-coated stents). New database tools to access biocompatibility data of the materials of construction in existing medical devices will facilitate the use of existing and new biomaterials for new medical device designs.

Introduction

Materials used in medical devices, particularly in those applications in which the device either contacts or is temporarily inserted or permanently implanted in the body, are typically described as biomaterials and have unique design requirements. The National Institute of Health Consensus Development Conference of November 1982 defined a biomaterial as “any substance (other than a drug) or combination of substances, synthetic or natural in origin, which can be used for any period of time, as a whole or as a part of a system which treats, augments, or replaces any tissue, organ, or function of the body” (Boretos and Eden, 1984, pp. 27–88, 128–132, 193–253).

The required material properties are determined by the specific device application and the functional life of the device, which ranges from temporary use to permanent implant. Devices can be used in (1) blood-contacting applications such as extracorporeal devices that remove and return blood from the body, devices that are inserted into a blood vessel, or devices that are permanently implanted; (2) soft-tissue device applications, such as soft-tissue augmentation; (3) orthopedic and dental applications for joint, bone, and tooth replacement and repair, (4) specific organ applications (e.g., neural); and (5) scaffolds for tissue engineering for tissue and organ replacement.

Materials for medical devices can be characterized as synthetic polymers, biodegradable polymers, bioactive materials, natural macromolecules (i.e., biopolymers), metals, carbons, and ceramics (Boretos and Eden, 1984; Helmus and Tweden, 1995; Helmus, 2003). They can be implanted for permanent replacement, as in an artificial heart valve or hip prosthesis, or for temporary use, such as an intravenous catheter or bone plates and rods. The sterilized device, and by default, the materials of which it is constructed, need to meet basic biocompatibility requirements, generally as defined by the ISO 10993 standards, to be nontoxic, nonthrombogenic, noncarcinogenic, nonantigenic, and nonmutagenic (Helmus, 2003). In blood-contacting applications, it must be nonthrombogenic to mitigate complications from thrombi and emboli. Potential complications will vary with a device and its application. Biodegradation and infection become increasingly important in longer term applications such as central venous catheters and permanently implanted devices. Because of the large surface area in extra-corporeal circuits, activation of biologic pathways, such as the coagulation, fibrinolytic, and complement pathways, may be magnified. Patients who are treated by extracorporeal methods (e.g., hemodialysis) are repeatedly exposed to leachable plasticizers and sterilant residuals.

Many devices, such as heart valves, artificial hearts, and hip implants are constructed of multiple materials. Joining methods can affect material properties that can reduce strength, fatigue life, and biostability. The material’s form and size, how it interfaces with the body, and its required duration of use will determine its required properties. One material property alone is unlikely to lead to a successful and durable device, whereas a lack of a single key property can lead to failure.

Coatings for improved biocompatibility and as carriers for drug delivery have an increasingly important role. Bioactive materials, which tend to use the nature of natural material or mimic natural materials, have applications in orthopedic implants to enhance bone attachment, antimicrobials to mitigate infection, and antithrombotics to mitigate thrombus. Drug–polymer combinations have been used in drug-eluting stents, heparin-release coatings for catheters, and steroid-releasing electrodes for pacemakers (Helmus and Tweden, 1995; Ranade et al., 2004; Ranade et al., 2005; Stokes, 1987). These drug-eluting devices are representative of combination devices that have the potential to create potent new therapies by using the best properties of drug-device, biologic-device, or drug-biologic combinations. The Food and Drug Administration’s Office of Combination Products (OCP) has broad responsibilities covering the regulatory life cycle of these combination products and will determine which Center has primary regulatory responsibility (Helmus, 2007). For example, the drug-eluting stent is primarily regulated by Center for Devices and Radiological Health, but Center for Drug Evaluation and Research has secondary responsibility for the analysis of drug content and compounding and manufacturing requirements.

The phenomena controlling the bioresponse are basically wound healing in the presence of a sterile medical device. The outcome of this healing process can have profound implications on the success of a device and can depend on material properties such as texture, crystallinity, wettability, surface chemistry, cytotoxic leachables, and degradation products (Andrade et al., 1987; Brash, 2000; Helmus and Tweden, 1995). These properties determine primarily the interaction between the materials and proteins in the biological environment, and subsequently, the interactions with the cells and tissues. The biologic response to materials, e.g., inflammation and thromboresistance, is an important consideration in the design of medical devices. Chronic inflammatory responses resulting in a thick fibrous capsule and the persistence of white cells, is undesirable and can lead to damage to surrounding tissue and to failure of the device. Leachables can cause local cytotoxicity and result in inflammation. Hypersensitivity reactions can occur to corrosion products and residual monomers, plasticizers, additives such as antioxidants, and degradation products. Cytotoxic leachables and degradation products, which may exhibit systemic effects if the dose is high, may result from the fabrication and sterilization methods used as well as ambient degradation by processes such as hydrolysis and oxidation over time (Coury et al., 1988; Stokes, 1987; Takahara et al., 1992). Contamination by bacteria, endotoxins (the breakdown products of gram-negative bacteria), and particulate debris can have profound effects on inflammatory responses (Helmus et al., 1986). These responses are generally a matter of handling, processing, and minimizing wear and corrosion in vivo. The lack of bacteriological contamination can be designated as an incoming requirement on materials from a vendor; however, wear and corrosion debris are inherent properties of materials and are a matter for appropriate materials selection.

Biostability refers to the ability of a material to resist biodegradation mechanisms and maintain its properties in situ. Degradation may result from hydrolysis, oxidation, enzyme catalyzed enhancement of hydrolysis, oxidation, lipid absorption, swelling, and calcification. Biomaterials with enhanced compatibility will combine new materials that have negligible leachables and exceptional biostability to mitigate adverse biologic responses to leaching of additives and breakdown products. Styrene-isobutylene-styrene triblock elastomer, used as the carrier for paclitaxel in the drug-eluting stents (Ranade et al., 2004; Ranade et al., 2005), is an example of this type of new-generation material and is described in the last section of this article.

Thromboresistance relates to the tendency of a material to reduce thrombus or emboli formation by formation of platelet-based and/or fibrin-based clots. Thrombi can form a nidus for coagulation, and they can also form a site that is prone to bacterial colonization and infection. Consumption of blood elements may be an indication of microemboli and activation of thrombotic mechanisms and is undesirable. Many bioprostheses, such as the bioprosthetic pericardial heart valve, are considered thromboresistant, whereas mechanical heart valves made from a variety of materials require permanent anticoagulation therapy. The effect of design and materials on thrombosis is difficult to separate in these cases. Materials such as poly(ester) fabrics are moderately thromboresistant but are suitable for their application as vascular grafts larger than 6 mm in diameter. Intimal hyperplastic responses resulting in the excess thickening of vascular tissue limit the use of synthetic small-diameter vascular grafts (Boretos and Eden, 1984) and result in the chronic closure of vessels after angioplasty.

Basic schemes for testing the acceptability of materials in terms of cytotoxicity, hemolysis, and mutagenicity can be found in the following standards and guidelines: American Society for Testing and Materials (ASTM) F-748 and the International Standards Organization 10993 standards; see Table 1. These documents provide a method of testing by device application (Helmus, 2003).

Medical Materials Information

Materials can be classified in a variety of different ways. The following, which is suitable for medical devices, sorts by type and application: synthetic polymer, biodegradable materials, tissue-derived materials, bioderived macromolecules, passive surface coatings, bioactive and tissue-adhesive materials, metals, ceramics and glassy carbons, composites, and nano materials. Table 2 gives examples of materials in each category, a medical device in which it is used, a list of ISO 10993 tests that it passed when fabricated as part of that medical device, and literature citations on its blood and soft-tissue compatibility. These data were extracted from ASM International’s Materials for Medical Devices Database, Cardiovascular Implant Materials Module (ASM International and Granta Design, 2007).

The database is an extensive resource, containing the engineering and biological performance of materials used in implantable cardiovascular devices as well as information about compatible coatings and drugs, manufacturing processes, and an extensive database of relevant published literature. The data are comprehensively cross-linked and fully traceable to original sources. The database can be used for information retrieval and selection of materials, drugs, and coatings for combination devices.

Table 3 summarizes the types of biocompatibility issues that might be a consideration in each category of biomaterials described below. These considerations are general and are influenced by the nature of the material (e.g., biostable vs. biodegradable) and application (e.g., soft-tissue, blood, or hard-tissue applications). The issues highlighted are the ones of particular importance to that category. The physical integrity and failure of devices have profound influence on the safety and efficacy of the device and are therefore categorized in this table.

Synthetics

Commonly available synthetic polymers are used in applications such as sutures, housings for extracorporeal devices (e.g., blood oxygenators, hemodialysis, and plasmapheresis devices), vascular grafts, heart-valve stents, abdominal patches, periodontal patches, and low-cost, high-volume tubing, connectors, and bags.

Examples include poly(amides), used as suture materials; poly(vinyl chloride) (PVC),¹ used as tubing and bags for the storage of blood and pharmaceutical products; poly(ethylene terephthalate) textiles, used as large-diameter vascular graft materials and as sewing cuffs on mechanical and biological heart valves; polymethylmethacrylate (PMMA), used as a fixation cement for the orthopedic prosthetics and for housings for extra-corporeal devices; and poly(tetrafluoroethylene) (PTFE), used extensively as an expanded membrane material for medium-diameter vascular grafts, abdominal patches, periodontal membranes, and as anterior-cruciate-ligament prostheses (Helmus, 2003). These materials tend to exhibit structural stability, relative biocompatibility, and low cost. Some vendors supply specifically designated biomedical grades. Master files are kept on the material production, and the vendors usually certify the material bio-compatibility based on standardized testing that shows that the materials as supplied are noncytotoxic and stable in the biological environment for certain periods of time and under certain conditions. Because of ongoing concerns with medical liability, some materials suppliers have limited the availability of their materials for use in permanent medical devices.

Some of the unique properties of synthetic materials are being used in new-generation devices. Hydrogel coatings, such as poly(ethylene oxide), are used for blood contact because of low levels of protein adsorption and their exceptional lubricity (Helmus and Hubbell, 1993). Poly(ether urea urethanes) are an example of a thermoplastic elastomer with excellent fatigue resistance. This material is used in the pumping bladder of the artificial heart. Highly oriented and highly crystalline poly(ethylene terephthalate) film is used as a balloon in certain angioplasty catheters because of its extraordinary bursting strength (Helmus and Hubbell, 1993). Table 3 summarizes the issues related to synthetic polymers.

Biodegradables

Biodegradable biomaterials are of high interest because of their ability to be absorbed gradually by the body (Kohn et al., 2004). The property of biodegradation in the biological environment makes these materials particularly appropriate for applications that are temporary in nature. These applications would normally require surgical removal.

Biodegradable products must have breakdown products that are nontoxic and eliminated by the body’s metabolic pathways. The most widely used biodegradable materials are homopolymers or copolymers of alpha-hydroxy acids, such as lactic and/or glycolic acids (Williams, 1981). These materials can be formulated to degrade with a half-life for mass loss ranging from a few months to a few years. They are widely used as bioresorbable sutures and carriers for drug-eluting stents.

Surface-erodible polymers are hydrophobic and are used to maintain the device’s physical strength for longer periods of time or to approach a zero-order release rate of pharmaceutical agents formulated into these surface-erodible polymers (Kohn et al., 2004). Examples include the polyanhydrides and polyorthoesters. Table 3 summarizes the issues related to biodegradables.

Tissue-Derived Materials

Processed tissues of human or nonhuman origin are used for ligaments, arteries, veins, and heart valves. Biodegradation and calcification during a period of 10 to 15 years has been an ongoing issue. Biologically derived materials are particularly susceptible to biodegradation mediated by proteolytic enzymes from plasma or from adherent cells. Calcification, seen particularly in biologically derived materials such as the bioprosthetic heart valve, can lead to stiffening and tearing of the bioprosthetic heart-valve cusps (Levy et al., 2003; Carpentier et al., 2007). Newer multiple-step processes entail treating the tissue to reduce antigenicity and to increase longevity in vivo by enzyme digestion, detergent extraction, and/or cross-linking with glutaraldehyde or other bifunctional agents. Significant efforts in reducing calcification have been demonstrated with ethanol and aluminum chloride treatments (Levy et al., 2003) as well as improvements in both calcification and thromboresistance with surfactant and alcohol treatment (Carpentier et al., 2007). Table 3 summarizes the issues related to tissue-derived materials.

Bioderived Macromolecules

Purified macromolecules are used for cardiovascular and soft-tissue applications. Collagen, both from human and nonhuman sources, is used as a space filler in cosmetic surgery, as a coagulation-inducing material, as a matrix to promote healing, and as a surface-treatment to make textile vascular grafts non-porous. Hyaluronic acid is being used as a coating to increase the lubricity of catheters and as an injectable into joints to reduce inflammation. Phosphorylcholine-derived polymers have been used to produce thromboresistant and biocompatible surfaces (De et al., 2002; Galli et al., 2001; Rose et al., 2004; Malik et al., 2001; Goreish et al., 2004). Human fibrin is used as a sealant and space filler in vascular and plastic surgery. Table 3 summarizes the issues related to bioderived macromolecules.

Passive Surface Modifications and Coatings

Specialized polymer coatings (e.g., silica-free silicones, hydrogels, and fluorocarbons), used to improve biocompatibility, and in many cases, to increase lubricity, are being developed for several cardiovascular applications (Hoffman, 1987). Plasma etching and plasma polymerization have also been used to modify surface properties. For example, the surface modification of vascular graft materials with nonpolymerizing gas plasmas (such as argon, oxygen, or nitrogen plasmas) has been observed to increase wettability and to generally increase the extent of cell attachment to materials. Treatment with a polymerizing gas plasma, such as tetrafluoroethylene, has been used to place a very thin, highly cross-linked polymer over-layer on a variety of base polymer substrates. These processes allow modification of surface properties without changing the bulk physical properties of the materials. Ultra low temperature isotropic (ULTI) carbon is used to modify Dacron polyester sewing cuffs and vascular grafts to improve their “blood compatibility” properties (Haubold et al., 1981). Table 3 summarizes the issues related to surface coatings.

Bioactive Coatings and Tissue Adhesives

Bioactivity refers to the inherent property of some materials to participate in specific biological reactions. Bioactive coatings may be formed from molecules that prevent blood clotting or initiate the enzymatic degradation of thrombus. Heparin coatings have been applied on cardiovascular implants, including stents, and annuloplasty rings. A heparin surfactant coating on polyester fabric of annuloplasty rings was shown in an arteriovenous shunt model to significantly reduce thrombus and platelet uptake (Helmus and Scott, 1999). Some negatively charged surfaces initiate the degradation of complement components with the potential for fewer side effects for extracorporeal treatments such as dialysis (Chenoweth, 1987). Cell-adhesion peptides and proteins are being investigated for enhancing endothelialization and soft-tissue adhesion (Tweden et al., 1995). Antimicrobial surfaces have been fabricated by immobilizing broad-spectrum antimicrobials such as silver, silver sulfadiazine, or specific antibiotics.

Bioactive coatings for orthopedic and dental-implant applications consist of calcium phosphate ceramics. These materials promote biological fixation by direct bonding with bone because of their chemical similarity with bone mineral (Cook et al., 1991). Interactions with the glycosaminoglycan molecules allow cellular deposition of collagen, which functions as a scaffold for mineralization.

Tissue adhesives such as methyl cyanoacrylates were used before the 1960s in the United States, but the hydrolytic breakdown product was formaldehyde, which is cytotoxic. This resulted in a greatly restricted use of cyanoacrylate. Different cyanoacrylate analogues, such as octyl-2-cyanoacrylate, are currently being evaluated and do not appear to demonstrate cytotoxic responses (Nitsch et al., 2005).

Fibrin glue is being investigated for producing microvascular anastomoses (Amrani et al., 2001) and controlling excessive bleeding by acting as a hemostatic agent. Table 3 summarizes the issues related to bioactive coatings.

Metals and Metallic Alloys

Commonly used alloys include austenitic stainless steels, cobalt-chrome-molybdenum (Co-Cr-Mo), tantalum, and titanium. Austenitic stainless steels, Co-Cr-Mo alloys, titanium, and titanium alloys are the preferred metals for orthopedic and dental applications.

Although stainless steels are used for permanent implants, they have shown that nickel-ion release can result in nickel hypersensitivity. Austenitic stainless steel is widely used in guidewires for angioplasty and angiography catheters, endovascular stents, fracture plates, nails, screws, and joint replacement (Helmus, 2003).

Titanium alloys are used for heart-valve and artificial-heart structural components because of their low density, high strength, low modulus (stiffness), low corrosion rate, and lack of cytotoxic effects. Titanium and its alloys are also used for pacemaker cases, fracture plates, nails and screws, and joint-replacement packaging for electrical stimulators because of these same properties (Helmus, 2003).

Endovascular stents can be fabricated from titanium, tantalum, nickel-titanium shape-memory alloys, austenitic stainless steel, and cobalt chrome. These devices can keep a vessel from rapidly closing after angioplasty if plaque rupture occurs. Anticoagulation and antiplatelet therapy is required for a few months with these devices. Most stents are crimped onto the end of an angioplasty catheter and expanded by the balloon at the site of the lesion to restore blood flow. Furthermore, the stent reduces but does not necessarily eliminate the restenosis that occurs because of the hyperplastic response of the lesion after injury caused by angioplasty. Other designs are self-expanding and use the springlike property of the metallic alloy to be positioned. Nickel–titanium alloys are typically used in these devices.

Co-Cr alloys are used for dental implants, bone plates, wires, screws, nails, joint-replacement parts, and self-expanding stents and in heart valves and rings because of their corrosion resistance, fatigue resistance, and strength (Helmus, 2003). Table 3 summarizes the issues related to metal alloys.

Ceramics and Glassy Carbons

Ceramics have been used extensively in dental and orthopedic applications (Hench and Best, 2004). Specifically, dense, high-purity alumina has been used as the ball and socket of total-hip endoprostheses (Griss and Heimke, 1981). Alumina has also been used in dental implants. Dense hydroxylapatite ceramics have been used in jaw reconstruction for maintenance of the alveolar ridge (Swart and Groot, 1987). Granules of hydroxylapatite have been used to fill bony, periodontal, and alveolar ridge defects.

Carbons have been widely used as heart-valve components, particularly as leaflets in mechanical valves, because of their resistance to degradation and their very high resistance to wear (Barenberg et al., 1990; Williams 1981; Ritchie et al., 1990). In particular, pyrolytic carbons, produced by the pyrolysis (thermal decomposition) of hydrocarbon vapors, have been used extensively. Glassy and pyrolytic carbon have also been used as dental implants. Table 3 summarizes the issues related to ceramics and glassy carbons.

Composites

Composite structures are particularly useful for meeting unique combinations of design requirements such as high strength, low density, and anisotropic properties. Many cardiovascular catheters use coextruded tubes with wires in the wall for steering the catheters and increasing their torsional rigidity (Rashkind and Wagner, 1981; Vandomael et al., 1986). Textile vascular prostheses have been coated with proteins such as collagen, gelatin, and albumin to eliminate the need for preclotting (Snyder and Helmus, 1988). The newer carbon-fiber composites based on engineering plastics are being investigated for orthopedic applications (Spector et al., 1990). They have the potential for use as structural components for the artificial heart and heart valves. Radio-opaque fillers such as barium sulfate are used to increase the visibility of polymers under X-ray. Table 3 summarizes the issues related to composites.

Nanomaterials

Nanomaterials are well suited for targeted drug delivery, molecular diagnostics, and imaging applications (both magnetic resonance imaging and X-ray imaging). Nanoporous materials will have applications in implants, as membranes (for example, for dialysis machines), and also in drug delivery. Nanostructured materials can enhance the biocompatibility and mechanical properties of medical devices, whereas drugs and nanostructured polymers can be combined to control the rate at which the drug is released in yet another drug-delivery application. The unique mechanical properties of nanostructured and nanocomposite materials (such as high strength and shape-memory properties) are also invaluable for implants and catheter devices (Helmus, 2007).

The TAXUS drug-eluting stent was shown by atomic force microscopy to have nanostructured microphase separation of the styrene-isobutylene-styrene triblock copolymer. The drug, paclitaxel, forms 20- to 30-nm particles that were typically in the styrene phase (Ranade et al., 2004; Ranade et al., 2005).

There are many unknowns about the potential safety effects of nanomaterials, particularly nanoparticulates. These effects relate to their uptake in the reticuloendothelial system (e.g., lung, spleen, liver), the ability to cross cell membranes, the potential to induce necrotic cell death or apoptosis, and the ability to interact at the level of cellular receptors (Helmus, 2007). Table 3 summarizes the issues related to nanomaterials.

Case Study of Sibs as a Vascular Compatible Drug-Delivery Matrix

The soft elastomeric styrene-isobutylene-styrene triblock copolymer, SIBS, is a polymeric carrier that meets stringent criteria enabling the development of a successful drug-eluting stent technology (Ranade et al., 2004; Ranade et al., 2005). SIBS exhibits biological, chemical, and physical properties consistent with good stent performance and forms the basis of the enabling technology and successful commercialization of Boston Scientific’s TAXUS drug-eluting stent. Some of the key properties of SIBS are summarized from the data extracted from the Materials for Medical Devices Database (ASM International, 2006); see Figure 1. Polymeric coatings for drug delivery from stents need to satisfy physical and biological criteria. Two of the enabling properties that allow SIBS to be used as a drug-delivery carrier are exceptional chronic biostability and vascular compatibility. One assessment of the biostability of explanted TAXUS stents from porcine coronary studies showed no change in molecular weight after 360 days after implant. Vascular compatibility was assessed by implantation in porcine coronary arteries. The tissue response to the SIBS is equivalent to that of the control stent without a polymer coating; see Figure 2. These enabling properties, in conjunction with the ability to delivery paclitaxel at acceptable rates and the ability to coat and sterilize coronary stents, allowed the successful development of a drug-eluting coronary stent (Ranade et al., 2004; Ranade et al., 2005).

Conclusion

The materials used in building a medical device must meet stringent functional requirements. Included in these requirements are biocompatibility concerns, a need to address what tissues the device interfaces with in the body and the biologic response that can result from this interaction, engineering properties, and compatibility with suitable combinations of coatings and elutable drugs. Materials selection made within the context of functional requirements will dramatically increase the safety and effectiveness of the device. Understanding the historic context of materials used in medical-device design and the bio-compatibility of these materials facilitates selection decisions in the design of new devices. New database tools allow rapid review of the biocompatibility of materials used in existing medical devices and all other important associated information. Furthermore, the evolving technology of highly biostable, bioactive, and drug-eluting biomaterials allows control of the healing response to improve safety and efficacy of implantable medical devices.